Discovery of highly potent and selective EGFRT790M/L858R TKIs against NSCLC based on molecular dynamic simulation

Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). There have been three generation drugs developed to treat of NSCLC. The third-generation EGFR tyrosine kinase inhibitors (TKIs) Rociletinib and Osimertinib (AZD9291) achieved remarkable clinical efficacy. However, due to the inhibitory activity against the wild-type EGFR, the side effect of associated skin rash and gastrointestinal toxicity appeared. Thus, there is still an urgent need to develop novel inhibitors with potent inhibitory activity and high selectivity for T790M-containing EGFR over EGFRWT. Herein, guided by the molecular dynamic simulation results, a series of potent and selective Osimertinib derivatives were designed, synthesized and evaluated. The promising compounds 7f, 7g, 7k, 7m and 7n demonstrated excellent kinase inhibitory activity and high selectivity for EGFRT790M/L858R mutant. The selectivity of 7m to EGFRT790M/L858R was the highest in the current known compounds near to 2500-fold. In addition, the compound 7m showed considerable activity against NCI-H1975 and HCC827 cells, arrested NCI-H1975 cell cycle at the G2/M stage and significantly induced apoptosis in NCI-H1975 cell. These encouraged results indicated that 7m will be used as a candidate targeting EGFRT790M/L858R for further pharmacodynamic and pharmacokinetic studies, and all these studies provide important clues for the discovery of potent EGFRT790M/L858R inhibitors with high selectivity.